KR20040075075A - Formulations - Google Patents

Abstract

The present invention relates to pharmaceutical compositions for oral administration of active compounds.

Description

Formulation {FORMULATIONS}

The present invention relates to pharmaceutical compositions for oral administration of the active compounds.

The active compounds to be used in the present invention are 2- [4- (diphenylmethyl) -1-piperazinyl] -acetic acid and amides thereof, as well as their pharmaceutically acceptable salts, geometric isomers, Enantiomers, diastereomers and mixtures thereof.

Formula 1

Where

R ₁ is a -COOH group or a -CONH ₂ group,

X ₁ and X ₂ each independently represent a hydrogen atom, a halogen atom, a linear or branched C ₁ -C ₄ alkoxy group or a trifluoromethyl group.

The compound according to formula 1 is orally active and is a selective histamine H ₁ -receptor antagonist. Such compounds are described in EP 0 058 146, the contents of which are incorporated herein by reference. Examples of such compounds are cetirizine in dihydrochloride form sold under the trade name Zyrtec®, its (S) enantiomer, levocetirizine in dihydrochloride form sold under the trade name Xyzal® and efletide in dihydroxychloride form. Contains lysine.

A serious problem encountered with oral formulations of these active compounds is their taste caused by the bitter taste of the active compounds of formula (1). This is especially noticeable in chewable and fast dissolving formulations.

Several attempts have been made in the prior art to mask the bitter taste of the active agent as a whole.

For example, US Pat. No. 5,244,881 teaches that inclusion of imipramine or its derivative, trimipramine, in cyclodextrin may mask the bitter taste of the active agent. Inclusion complexes are prepared by dissolving imipramine or trimipramine and cyclodextrin in a small amount of water or solvent, carefully mixing the resulting mixture and evaporating the mixture.

However, masking the taste is not always sufficient to obtain a pharmaceutical composition that tastes good. Good aesthetics usually require the addition of a polyol to the composition. As used herein, the term "polyol" includes, but is not limited to, xylitol, mannitol, sorbitol, dextrose, sucrose, lactose, maltodextrin, alpha cyclodextrin, beta cyclodextrin, gamma cyclodextrin, and polysaccharides. It is not. Mannitol has proved to be a suitable material, particularly for improving the aesthetics of formulations containing the active compound of formula (I). However, such compositions have significant disadvantages. In the presence of certain polyols comprising mannitol, the compound of formula 1 can lead to the undesirable reaction products described, for example, in EP 0 811 374 A1. Side reactions are increased by the presence of water and / or an increase in temperature. Thus the presence of mannitol and other polyols can cause stability problems for the compounds of formula (I).

To date, to avoid undesired reaction products, there is no choice but to prevent the presence of such polyols in the composition or to coat the active compound of formula 1 with, for example, cellulose or acrylate polymers prior to formulation.

In the first case, the use of other excipients such as microcrystalline cellulose impairs the taste of the tablet due to the fact that microcrystalline cellulose is not completely dissolved in water and may leave a sandy feeling in the oral cavity.

In the second case, the coating thickness needed to avoid interaction between the active compound of Formula 1 and the polyol (s) hinders the rapid release of the drug from the pharmaceutical form.

EP 0 811 374 Al teaches that there should be no reactive alcohols comprising polyols in the entire dosage form. Therefore, polyols that improve aesthetics may not be used in the overall oral composition according to this description. Example 2 of EP 0 811 374 described to illustrate a preferred embodiment clearly shows the absence of a polyol which improves aesthetics; The only polyol present in these compositions is polyethyleneglycol, a high molecular weight polyol (MW 3350) that has a different function than taste masking.

It is an object of the present invention to overcome the disadvantages of loss of stability in the presence of polyols in a way that is tasty and avoids adverse changes in product performance.

The problem addressed by the present invention therefore improves the taste and aesthetics of oral compositions containing the active compound of formula 1 and the polyols that improve the aesthetics, while at the same time avoiding loss of stability to the active compounds and maintaining optimal release kinetics.

In general, the masking polyol is solid and has a molecular weight of less than 3000.

We have found that the loss of stability caused by the interaction of the polyol with the active compound of formula 1 correlates with a decrease in the molecular weight of the polyol.

Molecular weight of some polyols Polyol MW Xylitol 152.15 Mannitol 182.17 Sorbitol 182.17 Dextrose 198.17 Sucrose 342.30 Lactose 342.30 Maltodextrin 900.00 or more Alpha cyclodextrin 972.00 Beta cyclodextrin 1135.00 Gamma cyclodextrin 1297.00 Microcrystalline cellulose 36000

In general, low molecular weight polyols (see Table 1), such as xylitol, mannitol, sorbitol, dextrose or sucrose, are reactive or highly reactive, resulting in large amounts of undesirable reaction products. On the other hand, polyols having a high molecular weight such as cyclodextrin (see Table 1) have very low reactivity.

Surprisingly, this correlation between molecular weight and reactivity is not true for lactose. Lactose has the same molecular weight as sucrose but practically shows no reactivity with the active compound of formula (I).

Therefore, highly reactive polyols can be defined as polyols having a molecular weight of less than 300. Reactive polyols have a molecular weight of 300 to 950, except for lactose.

The inventors have also found that reactive or highly reactive polyols do not further result in reaction products of unacceptable amounts of undesired active compounds of formula (1) when the molar ratio of polyol to active compound does not exceed 10. In addition, when the molar ratio of the reactive or highly reactive polyol to the active compound of formula 1 does not exceed 5, the percentage of undesired by-products is further minimized.

On the basis of this finding, the technical problem is that according to the invention, the first formulation contains polyols at critical levels which are reactive or highly reactive with the active compounds of the formula (1), and which polyols are required to obtain a good taste for the second formulation. It can be solved by providing a composition prepared from two formulations, which contains but does not contain drug compounds. As a result, the formation of undesired reaction products is largely eliminated and the unpleasant taste is effectively reduced or masked.

The solution to this problem is very different from what is taught in EP 0 811 374 A1. This document teaches that dosage forms should be substantially free of reactive alcohol upon introduction of the fast-acting cetirizine component into the dosage form, after which the reactive polyol should be excluded from the overall composition. The alcohols described in EP 0 811 374 A1 perform a completely different function from the present invention, i.e. high molecular weight to promote the release of solvents (low molecular weight alcohols such as methanol, ethanol, isopropanol and glycerin) or pseudoephedrine. Act as a compound (polyethylene glycol). Low molecular weight alcohols are removed before adding cetirizine to prevent undesired reaction products.

According to the invention, the reactive polyol may be present in any amount in the second layer. Indeed, the presence of a solid polyol having a molecular weight of less than 3000 in the second formulation according to the present invention is required for improving the aesthetics essential for chewable or rapidly dissolving pharmaceutical compositions.

EP 0 811 374 A1 does not relate to taste masking since the dosage form is not intended to be dispersed in the oral cavity and must be swallowed completely.

Thus, the present invention is an oral pharmaceutical composition containing two or more separate formulations,

2- [4- (diphenylmethyl) -1-piperazinyl] -acetic acid and amides thereof as well as their pharmaceutically acceptable salts, geometric isomers, enantiomers, Containing an active compound selected from diastereomers and mixtures thereof, wherein the polyol having a molecular weight of less than 300 does not contain more than 10 molar ratios of the polyol and the active compound of formula 1;

The second formulation relates to an oral pharmaceutical composition containing at least one solid polyol (s) having a molecular weight of less than 3000 and no drug.

Formula 1

Where

R ₁ is a -COOH group or a -CONH ₂ group,

X ₁ and X ₂ each independently represent a hydrogen atom, a halogen atom, a linear or branched C ₁ -C ₄ alkoxy group or a trifluoromethyl group.

Solid polyols are defined as polyols that are not liquid at room temperature under atmospheric pressure.

In one preferred embodiment, the first formulation does not contain a polyol having a molecular weight of less than 950 except lactose of more than 10 molar ratios of the polyol and the active compound of formula (I). Since lactose does not have significant reactivity with the active compound of Formula 1, it may be present in higher ratios.

In another preferred embodiment of the invention, the first formulation does not contain a polyol having a molecular weight of less than 300 and a molar ratio of polyol and active compound of formula (I) greater than 5.

In a more preferred embodiment, the first formulation does not contain polyols having a molecular weight of less than 950 except lactose of more than 5 molar ratios of the polyol and the active compound of formula (I).

In even more preferred embodiments, the first formulation does not contain polyols having a molecular weight of less than 300.

In another even more preferred embodiment, the first formulation does not contain polyols having a molecular weight of less than 950 except for lactose.

As used in the present invention, the active compound of the formula (1) is 2- [4- (diphenylmethyl) -1-piperazinyl] -acetic acid and amide thereof having the formula (1) as defined above, and Non-toxic pharmaceutically acceptable salts, geometric isomers, enantiomers, diastereomers and mixtures thereof (racemates) thereof. In one preferred embodiment, the active compound of the first formulation is cetirizine dihydrochloride, levocetirizine dihydrochloride or epletirizine dihydrochloride.

The term drug includes active compounds of formula 1 and other drugs.

Preferably, the oral pharmaceutical composition contains only one active ingredient.

The polyols used in the second formulation typically have the ability to reduce the bitter taste of the active compound of formula 1 and to improve the aesthetics of the formulation. Examples include sorbitol, xylitol, mannitol, dextrose, sucrose, polysaccharides, preferably mannitol.

The formulations are prepared in the form of powders, granules, solutions or suspensions.

Solutions or suspensions are used to carry out the coating.

The first and / or second formulations also contain an alkalizing agent, preferably sodium citrate. Such agents also reduce the production of undesirable reaction products between the polyol and the active compound of formula (1).

The first formulation may contain one or more additional excipients such as colloidal anhydrous silica, microcrystalline cellulose, magnesium stearate, flavoring or coloring agents, or mixtures thereof.

The first formulation may also contain polyols in certain molar ratios that do not fall under the conditions of a particular molecular weight, as described above. The first formulation may further contain non-polyol sweeteners such as acesulfame K, aspartame, saccharin, saccharin sodium, cyclamate.

Flavoring agents suitable for use in the present invention include essential oils and synthetic oils such as citrus oil, fruit essences, peppermint oil, spearmint oil, cloves oil, presser balm, anise, eucalyptus oil and the like. Other artificial flavors known to those skilled in the art are also within the scope of the present invention.

All oral composition forms including tablets, chewing gums, effervescent tablets or dry syrups are contemplated by the present invention.

Dry syrup is defined as a solid formulation such as, for example, a powder or granules that are orally administered after being added in dry syrup form or liquid.

Accordingly, the present invention relates to bilayer tablets, in certain embodiments, wherein each layer is made from one formulation.

The two powder formulations are mixed separately and then compressed in a double layer rotary tablet press.

The term compression is defined as the volume reduction of the powder bed due to stress application (see Goran Alderborn and Chryster Nystrom's literature "Pharmaceutical Powder Compression Technique"). , p.vii, Marcel Dekker, Inc., New York).

In another embodiment, the present invention relates to a triple layer tablet, in which the inactive layer isolates the layers prepared from the two formulations.

Tablet designs according to the invention can also be made from, for example, a "sandwich" design in which both sides of an inner layer made from one formulation are coated with layers made from the other formulation, or from an inner core made from one formulation and the rest of the formulation. Bilayer tablets having outer shells prepared, or multilayer tablets comprising further layers in addition to the first and second layers prepared from the first and second formulations.

Another embodiment of the present invention relates to a dry syrup consisting of a mixture of two formulations prepared in the form of granules, a formulation containing the active compound of formula 1 and a polyol (s).

In this case, the powder formulations are mixed separately and then pressed, ground and sieved separately to obtain two kinds of granules. These granules are mixed together to obtain the final product.

Compressing each formulation individually is desirable to produce an effective dry syrup.

The term compaction is defined as the transformation of a powder into a coagulated sample of a defined form by powder compaction (see Goran Alderborn and Cristiantzeb, literature "Pharmaceutical Powder Compaction Technique", p.vii, Marcel Dekker, Inc.). , New York).

Another embodiment of the invention relates to a chewing gum consisting of a coating made from a core and a second formulation, for example, made from a first formulation and additionally containing a gum base. Alternatively, the chewing gum may consist of a core made from the second formulation and additionally containing a gum base and a coating made of the first formulation.

The gum base used in the present invention for producing chewing gum can be any suitable gum base known in the art, including natural and synthetic gum bases.

All compositions according to the invention may contain one or more additional outer coatings.

If cyclodextrin is present, the molar ratio between cyclodextrin and the active substance of formula 1 ranges from 10: 1 to 1: 1.

The weight ratio of the first and second formulations is from 1:20 to 20: 1.

The composition according to the invention is dispersible in the oral cavity and does not require water in contrast to the dosage form described in EP 0 811 374 A1. For example, the compositions of the present invention are in the form of orally dispersible tablets (tablets that are placed in the mouth and disperse rapidly before swallowing) that can chew, bite or suck them.

Experimental results demonstrated that the composition according to the invention, which is dispersed in the oral cavity, is biologically equivalent to the swallowed dosage form.

Preferably, the compositions according to the invention are fast-acting formulations, ie pharmaceutical formulations which have little or no effect on the rate of dispersion of the active ingredient to the site of action.

Another embodiment relates to a process for the preparation of a composition according to the invention in which the first and second formulations are prepared separately and the two formulations are combined. The formulations are obtained with conventional techniques such as compression, direct compression, granulation, wet granulation, coating. Such techniques are known to those skilled in the art.

In addition, taste masking techniques can be used with the present invention. Masking properties can be obtained by applying masking techniques to one or both formulations.

The invention is illustrated by the following examples.

Example 1. Chewable Cetirizine Bilayer Tablet.

Two formulations were prepared separately. Tables 2 and 3 show the composition of these formulations.

Composition of Cetirizine.2HCl Formulation for Bilayer Purification ingredient Composition (mg / tablet) Cetirizine. 2 HCl 10.00 βcyclodextrin 82.50 Acesulfame K 3.50 Colloidal anhydrous silica 1.10 Microcrystalline cellulose 43.86 Flavor 0.80 Lactose Monohydrate 55.00 dyes 0.48 Magnesium stearate 2.76

Composition of Mannitol Formulation for Bilayer Tablets ingredient Composition (mg / tablet) Mannitol 241.21 Acesulfame K 4.69 Flavor 1.00 dyes 0.60 Magnesium stearate 2.50

The cetirizine and mannitol formulations were then compressed on a rotary bilayer tablet press (eg Courtoy 292/43).

Tablets were dispensed for 3 months at 25 ° C.-60% relative humidity (RH), 30 ° C.-60% RH, and 40 ° C.-75% RH in aluminum / aluminum blister (Alu / Alu blister) and high density polyethylene (HDPE) bottles. It was left. Table 4 shows the results of this stability study.

Stability Study of Chewable Cetirizine Bilayer Tablets Vessel Condition Cetirizine (%) Reaction product (%) HDPE Bottle 25 ℃ -60% RH 100.50 0.10 30 ℃ -60% RH 100.00 0.20 40 ℃ -75% RH 99.27 0.29 Alu / Alu blister 25 ℃ -60% RH 96.28 0.10 30 ℃ -60% RH 99.32 BLQ 40 ℃ -75% RH 99.99 0.22

BLQ: below quantification limit (= 0.1%)

Moisture content, resistance to crushing, disintegration time and dissolution kinetics were also measured and all tablets met all specifications under any storage conditions.

Example 2. Cetirizine Dry Syrup

Two formulations were prepared separately. Tables 5 and 6 show the compositions of these formulations.

Composition of Cetirizine.2HCl Formulation for Dry Syrup ingredient Composition (mg) A B C Cetirizine.2HCl 10.00 10.00 10.00 βcyclodextrin 82.50 82.50 82.50 Acesulfame K 3.00 3.00 3.00 Microcrystalline cellulose 279.00 83.70 0.00 Lactose Monohydrate 0.00 195.30 0.00 Sodium citrate 25.50 25.50 0.00 Sum 400.00 400.00 95.50

Composition of Mannitol Formulation for Dry Syrup ingredient Composition (mg) D Mannitol 399.60 Flavor 0.40 Sum 400.00

Formulations A, B, C and D were separately compressed, ground and sieved to obtain granules A ', B', C 'and D'. The final composition of the dry syrup was obtained by mixing granules A ', B', C 'and D' according to the proportions described in Table 7.

Dry syrup composition Composition Ingredient (mg) A ' B ' C ' D ' E 400.00 0.00 0.00 400.00 F 0.00 400.00 0.00 400.00 G 0.00 0.00 95.50 404.50 H 100.00 0.00 0.00 200.00

The dry syrup was left for 10 weeks at 25 ° C.-60% RH, 30 ° C.-60% RH, and 40 ° C.-75% RH in an aluminum / aluminum blister. Table 8 shows the percentage of undesired reaction products detected in the formulation.

Percentage of Undesired Reaction Products in Dry Syrup After 10 Weeks Composition Condition Reaction product (%) E 25 ℃ -60% RH 0.00 30 ℃ -60% RH 0.00 40 ℃ -75% RH 0.26 F 25 ℃ -60% RH 0.00 30 ℃ -60% RH 0.00 40 ℃ -75% RH 0.31 G 25 ℃ -60% RH 0.00 30 ℃ -60% RH 0.06 40 ℃ -75% RH 0.34 H 25 ℃ -60% RH 0.03 30 ℃ -60% RH 0.04 40 ℃ -75% RH 0.30

All formulations meet all specifications.

Example 3 Cetirizine Chewing Gum

The composition of the chewing gum consisting of the core containing cetirizine obtained by compression and the coating containing polyol is shown in Table 9.

Chewing Gum ingredient Composition (mg) core: Cetirizine.HCl 10.00 βcyclodextrin 100.00 Sword base 660.00 Aspartame 3.00 Acesulfame K 2.00 Colloidal silica 30.00 Talc 30.00 Magnesium stearate 20.00 Sweetener 65.00 Flavor 80.00 coating: Xylitol 382.50 Mannitol 85.00 Polyethylene Glycol 6000 10.00 Titanium dioxide 10.00 Arabic sword 10.00 Flavor 2.50 Carnauba Wax 0.0015

As in the case of bilayer tablets and dry syrups, the chewing gum meets the stability requirements.

Claims (22)

An oral pharmaceutical composition containing two or more separate formulations, 2- [4- (diphenylmethyl) -1-piperazinyl] -acetic acid and its amides as well as their pharmaceutically acceptable salts, geometric isomers, enantiomers, Containing an active compound selected from diastereomers and mixtures thereof, wherein the polyol having a molecular weight of less than 300 does not contain more than 10 molar ratios of the polyol and the active compound of formula 1; Oral pharmaceutical compositions in which the second formulation contains at least one solid polyol (s) having a molecular weight of less than 3000 and no drug Formula 1 Where R ₁ is a -COOH group or a -CONH ₂ group, X ₁ and X ₂ each independently represent a hydrogen atom, a halogen atom, a linear or branched C ₁ -C ₄ alkoxy group or a trifluoromethyl group. The composition of claim 1, wherein the first formulation does not contain a polyol having a molecular weight of less than 950 except lactose of more than 10 molar ratios of the polyol and the active compound of formula (I). The composition of claim 1, wherein the first formulation contains a polyol having a molecular weight of less than 300 and no molar ratio between the polyol and the active compound of formula 1 is greater than 5. 4. A composition according to any one of claims 1 to 3, wherein the first formulation contains no polyols having a molecular weight of less than 300. The method according to any one of claims 1 to 3, characterized in that the first formulation does not contain a polyol having a molecular weight of less than 950 except lactose of more than 5 in a molar ratio of the polyol and the active compound of formula (I). Composition. 6. The composition of claim 1, wherein the first formulation does not contain polyols having a molecular weight of less than 950 except for lactose. 7. The composition of claim 1, wherein the formulation is prepared in the form of a powder, granule, solution or suspension. 8. A composition according to any one of claims 1 to 7, wherein the polyol of the second formulation is mannitol. 8. A composition according to any one of claims 1 to 7, wherein the polyol of the second formulation is a polysaccharide. The composition of claim 1, wherein the one or more formulations further contain an alkalizing agent. The composition of claim 10 wherein the alkalizing agent is sodium citrate. The method of claim 1, wherein the first formulation further contains one or more excipients selected from cyclodextrins, colloidal anhydrous silica, microcrystalline cellulose, magnesium stearate, flavoring agents, or colorants. Composition. The composition of claim 1, wherein the first formulation further contains a non-polyol sweetener, such as acesulfame K, aspartame, saccharin, saccharin sodium or cyclamate. The composition according to claim 1, wherein the active compound of the first formulation is cetirizine dihydrochloride, levocetirizine dihydrochloride or epletirizine dihydrochloride. The composition of claim 1, wherein the composition is in the form of a chewing gum, tablet, or effervescent tablet. The composition of claim 15 in the form of a multilayer tablet, wherein each layer is made from one formulation. 17. The composition of claim 16, in the form of a multilayer tablet, wherein the inactive layer isolates the layers prepared from the two formulations. The composition of claim 15, wherein the composition is a tablet having an inner core made from one formulation and an outer shell made from the remaining formulation. The composition of claim 15, wherein the composition is A core made from the first formulation and further containing a gum base, and A chewing gum comprising a coating made from a second formulation. The composition of claim 15, wherein the composition is A core made from the second formulation and further containing a gum base, and A composition characterized by a chewing gum comprising a coating made from the first formulation. The composition of claim 1, wherein the composition is a dry syrup prepared from a mixture of two types of granules, one of the granules is made by pressing the first formulation, and the remaining forms of the granules are A composition, which is prepared by pressing the formulation. 22. A method of making a composition according to any one of claims 1 to 21, comprising separately preparing the first and second formulations and combining the two formulations.